Regulation Of Cell Proliferation By The Actin Cytoskeleton
Funder
National Health and Medical Research Council
Funding Amount
$607,795.00
Summary
The architecture of cells defines both their shape and function. It has been known for a long time that cell architecture controls the growth of cells and in particular their capacity to proliferate. We have identified part of the architectural system which controls this process. In this project we will establish how this works and its role in the body. This research will test whether this part of the cell�s architecture is a suitable drug target for the treatment of disorders in cell growth.
Targeting Chromosomal Instability By Metabolic Stress
Funder
National Health and Medical Research Council
Funding Amount
$612,652.00
Summary
The most intractable cancers gain and lose DNA as they grow, making them highly variable and drug resistant. We have found that mild disruptions to their use of energy can specifically kill cells with this kind of genetic instability. In this project we will characterize the mechanism by which metabolic stress affects cell division and the survival of genetically unstable cells. Our objective is to find treatments with no effects on normal cells that eliminate unstably dividing cancer cells.
Developing Cancer Therapies That Target Chromosomal Instability
Funder
National Health and Medical Research Council
Funding Amount
$644,126.00
Summary
A significant reason why late-stage cancers are hard to treat with drugs is because the tumour cells show genetic variability, always producing new variants that sooner or later get around the drugs. We intend to combat this by targeting the ability of cancer cells to vary genetically - we are discovering ways to specifically kill genetically unstable cells. This prevents the cancer from developing drug resistance as well as having less side effects on the patient's normal cells.
Characterising The Mechanisms That Control Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$335,616.00
Summary
Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as can ....Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as cancer.Read moreRead less
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less
HFP ACTIVATES PROTEOLYSIS OF POSITIVE CELL CYCLE REGULATORS TO INHIBIT CELL CYCLE PROGRESSION IN DROSOPHILA
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions bet ....Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions between two group of proteins, cell cycle activators and cell cycle inhibitors. Aberrations in cell cycle inhibitor proteins will cause excessive cell proliferation, the first step in the multi-step process of tumour development. It is important to understand the processes that normally inhibit cell proliferation, since cells undergoing more rapid cell cycles are much more likely to develop further errors in their genetic material and progress to later stage invasive tumours. This proposal focuses on a protein (FIR-Hfp) that we have shown to inhibit cell cycle progression in the vinegar fly (Drosophila Melanogaster), which is an excellent model organism for studying developmentally regulated cell proliferation. Furthermore, most cell cycle regulators are conserved in evolution, so the knowledge derived from these studies can assist with our understanding of how complex pathways might coordinate proliferation mammals. FIR-Hfp negatively regulates cell proliferation by down-regulating cycle activator proteins (dMyc and Stg). At present the mechanism for the inhibitory affect on these activators is not understood, but preliminary data suggests that FIR-Hfp might be involved in causing Stg and the dMyc activator protein (Hay) to be targeted for destruction. The aim of this project is to elucidate the mechanism by which Hfp regulates the activity of these potentially ocogenic factors, and thus gain a better understanding of the preliminary stages of tumour progression.Read moreRead less
Dual Targeting Of Myc And Apoptosis Pathways For Improved Blood Cancer Treatment Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$754,685.00
Summary
Cancer cells frequently possess defects in genes called MYC and BCL-2 that control their growth and survival. Our preliminary studies have shown that combining novel reagents that specifically target MYC plus BCL-2 leads to enhanced lymphoma cell killing. In the proposed research, we will further develop these reagents and evaluate their ability to treat blood cancer in mice. We expect our approach will provide new avenues for treating cancer patients that respond poorly to current treatments.
Mechanisms Of Mcl-1- And Bcl-2-mediated Resistance To Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$439,796.00
Summary
Anti-cancer therapies that target either the mitochondrial or death receptor pathways of apoptotic cell death are being developed and in clinical trials. In certain cancer cells, the tBid protein links the two pathways, making the death receptor pathway dependent on the mitochondrial pathway. Our studies will test how tBid links the two pathways and how the link might be bypassed, potentially indicating means of improving the effectiveness of treating cancer by targeting death receptors (e.g. TR ....Anti-cancer therapies that target either the mitochondrial or death receptor pathways of apoptotic cell death are being developed and in clinical trials. In certain cancer cells, the tBid protein links the two pathways, making the death receptor pathway dependent on the mitochondrial pathway. Our studies will test how tBid links the two pathways and how the link might be bypassed, potentially indicating means of improving the effectiveness of treating cancer by targeting death receptors (e.g. TRAIL).Read moreRead less
Manipulating Oncogenic-signalling Pathways In The Genesis And Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$601,484.00
Summary
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry is damaged in melanomas. This work will greatly accelerate the development of new therapi ....Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry is damaged in melanomas. This work will greatly accelerate the development of new therapies.Read moreRead less
Manipulating The B-RAF/MEK Pathway In The Genesis And Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry that is damaged in melanomas. This work will greatly accelerate the development of new th ....Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry that is damaged in melanomas. This work will greatly accelerate the development of new therapies.Read moreRead less